This project has continued to focus on investigations of the functional status of the serotonin (5-HT) neurotransmitter system in humans using 5-HT-selective agonists (e.g., m-chlorophenylpiperazine (m-CPP)) and antagonists (e.g., metergoline, ondansetron) as pharmacologic probes. In collaborative studies, Dr. E. M. Jacobsen found behavioral and neuroendocrine response differences to m-CPP administration between patients with seasonal affective disorder and matched control subjects. Many of these response differences were no longer present when the patients and controls were re-challenged with m_CPP following treatment- induced remission of their depressive symptoms. In laboratory studies related to serotonin, Dr. K.-Peter Lesch successfully isolated and sequenced a cDNA encoding the human brain vesicular monoamine transporter (VMT). Although the human VMT is highly homologous (greater than 90%) with the rat brain VMT, an extensive sequence divergence was found in one region, a large lumenal loop located between the first two transmembrane domains. A structurally identical VMT was found to be expressed in human platelets. Dr. Lesch also found that human platelets express a cell membrane serotonin transporter that is identical to the transporter found in human brain. In other studies, Dr. A.M. Andrews found that the prolonged (up to 6 months in duration) depletion of brain serotonin produced by the novel analogue of the parkinsonism-producing dopamine neurotoxin, MPTP, 2'amino-MPTP, could be prevented by pretreatment with fluoxetine or clorgyline.